Enzyme catalysis molecular dynamics simulation

Wang S, Hu P, Zhang Y (2007) Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis the case of histone lysine methyltransferase set7/9. J Phys Chem B ASAP... 

Another illustration of the power of molecular dynamics simulation can be drawn from the sphere of enzyme catalysis. Many enzyme-catalyzed reactions proceed at a rate that depends on the diffusion-limited association of the substrate with the active site. Sharp et al. [28] have carried out Brownian dynamics simulations of the association of superoxide anions with superoxide dismutase (SOD). The active center in SOD is a positively charged copper atom. The distribution of charge over the enzyme is not uniform, and so an electric field is produced. Using their model, Sharp et al. [28] have shown that the electric field enhances the association of the substrate with the enzyme by a factor of 30 or more. Their calculations also predict correctly the response of the association rate to changes in ionic strength and amino... 

Figure 25 The middle layer of the model enzyme used by Bagdassarian and coworkers to examine the role of vibrations in promotion of catalysis. C is the catalytic subunit, and S the substrate. Molecular dynamics simulations were used to assess the catalytic efficiency of enzymes that varied in the number of flexible and stiff linkages between neighboring subunits in the white box. P (phantom) and N (neutral) subunits were not varied during the simulation. Reproduced with permission from G. S. B. Williams A. M. Hossain S. Shang D. E. Kranbuehl C. K. Bagdassarian, J. Theor. Comput.

It has been frequently suggested that dynamical factors are important in enzyme catalysis (Ref. 9), implying that enzymes might accelerate reactions by utilizing special fluctuations which are not available for the corresponding reaction in solutions. This hypothesis, however, looks less appealing when one examines its feasibility by molecular simulations. That is, as demonstrated in Chapter 2, it is possible to express the rate constant as... 

Quantum dynamics effects for hydride transfer in enzyme catalysis have been analyzed by Alhambra et. al., 2000. This process is simulated using canonically variational transition-states for overbarrier dynamics and optimized multidimensional paths for tunneling. A system is divided into a primary zone (substrate-enzyme-coenzyme), which is embedded in a secondary zone (substrate-enzyme-coenzyme-solvent). The potential energy surface of the first zone is treated by quantum mechanical electronic structure methods, and protein, coenzyme, and solvent atoms by molecular mechanical force fields. The theory allows the calculation of Schaad-Swain exponents for primary (aprim) and secondary (asec) KIE... 

Hwang et al.131 were the first to calculate the contribution of tunneling and other nuclear quantum effects to enzyme catalysis. Since then, and in particular in the past few years, there has been a significant increase in simulations of QM-nuclear effects in enzyme reactions. The approaches used range from the quantized classical path (QCP) (e.g., Refs. 4,57,136), the centroid path integral approach,137,138 and vibrational TS theory,139 to the molecular dynamics with quantum transition (MDQT) surface hopping method.140 Most studies did not yet examine the reference water reaction, and thus could only evaluate the QM contribution to the enzyme rate constant, rather than the corresponding catalytic effect. However, studies that explored the actual catalytic contributions (e.g., Refs. 4,57,136) concluded that the QM contributions are similar for the reaction in the enzyme and in solution, and thus, do not contribute to catalysis. 

Static quantum mechanical calculations have respectable energetic accuracy but are Hmited to a single geometry per calculation. On the other hand, classical molecular dynamics calculations are able to take into account dynamic effects which might be critical to enzyme catalysis and are difficult to deal with by conventional quantum mechanics these calculations employ empirical force fields, however. The Car-Parrinello molecular dynamics method (CPMD) [41, 42], though, has successfully incorporated the accuracy of quantum mechanical calculations into dynamics simulations at a reasonable cost. CPMD 3.5 [43] has been employed by our group to investigate various model systems related to the ODCase mechanism [44]. 

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